Meta-analysis of Studies Investigating Association between FTO Gene Polymorphisms and Breast Cancer

Back Objectives: The aim of this study is to pool the result of studies on the association between FTO gene polymorphisms and breast cancer (BC). Material and Methods: We searched PubMed, Embase, Science Direct, Scopus, web of science, and Cochran to identify studies investigating the associations between the rs1477196 and rs9939609 polymorphisms and BC risk. We pooled adjusted odds ratios (ORs) as overall. ORs were estimated using a random effects model. Results: In total, 16 articles were included in the final analysis. Considering the dominant model of inheritance, there was an inverse association between the rs1477196 polymorphism and BC (OR 0.76 [0.64- 0.91]). There was not observable heterogeneity (I2: 0.0%, P=.867), but with a small study effect (b=1.19, P=.03) in this analysis. Moreover, there was not any association between the rs9939609 polymorphism and BC (OR 0.98 [0.79- 1.2]). There was not observable heterogeneity (I2: 23.1%, P=.27) and small study effect (b=-3.817, P=.303) in this analysis. Conclusions: The carriers of rs1477196 polymorphism of FTO are at lower risk for BC. Carriers of Rs9939609 polymorphism had no association with Breast cancer risk.

 Introduction

Obesity increases the risk of breast cancer by 30-50% in women after menopause [1]. In a 16-year cohort study on 900,000 healthy people, obesity caused 57,000 cancer related deaths. Additionally, it has been shown that the death rate from cancer in persons with the highest BMI was twice that of women with the lowest BMI [2]. Genetic, behavioral and environmental factors are among the most important factors associated with both obesity and breast cancer [3]. There are a variety of mechanisms for linking obesity and cancer risk. Obesity increases insulin resistance, and hyperinsulinemia increases the secretion of the growth hormone, which in turn stimulates the production of carcinogens, mitogenesis, and triggers routs to oxidative stress and inflammatory process [4]. Several genes have also been studied with regard to the association between obesity and cancer; the most scientifically plausible one is FTO (fat mass and obesity-related). The association between FTO and obesity and cancer has been confirmed through the presence of single-nucleotide polymorphisms (SNPs). There are several SNPs in the FTO gene that recent studies have shown an etiologic role in incidence of breast cancer. Some of these polymorphisms include: rs9939609, rs17817449, rs8050136, rs1477196, rs6499640, rs16953002, rs11075995, and rs1121980 [5-6]. This systematic review and meta-analysis aims to 1) identify all FTO gene polymorphisms involved in the risk of breast cancer or prognosis of breast cancer, and 2) to pool the studies that report a quantitative measure of association between a FTO polymorphism and breast cancer risk and progression.

Materials and Methods Search Databses and Strategy

In the current study, all of the published articles related to FTO gene polymorphisms and breast cancer until 20 January, 2019 were searched in the Pubmed, embase, Science Direct, Scopus, web of science, and Cochran databases. Key words such as “fat mass and obesity associated gene” and/or “FTO”, “breast cancer” and/or “breast neoplasm” and/or “polymorphism” and/or “SNP” were used in order to obtain the related articles. All articles collected in the electronic search process as well as the references used in these articles were reviewed. Irrelevant, non-English, and inappropriate articles were excluded from systematic review process based on the following inclusion and exclusion criteria.

Inclusion and exclusion criteria

Studies which have quantitatively investigated the association between FTO gene polymorphisms and breast cancer using case-control studies and odds ratio and confidence interval indicators. Studies focused on the other cases as well as those which had investigated outcomes other than breast cancer (e.g., obesity or other cancers), and studies which had investigated breast cancer in men were excluded from our review study.

Assessment of methodological rigor

At this stage, studies conducted to investigate the association between FTO gene polymorphisms and breast cancer were selected. The quality of studies was independently assessed by 2 persons (SD and MGh), and if two assessors do not agree with each other, the assessment was completed as a discussion with a third person (SAMJ). The irrelevant articles were excluded from the intended articles. The full text of the articles known as appropriate in this study was investigated. In order to assess the quality of the studies’ methodology, the standardized quality assessment method for clinical trials (The EPOC Risk of Bias Tool) was used [7]. In addition, the preferred reporting items for systematic reviews and meta-analyses (PRISMA) were used in this study [8]. Figure 1 shows the selection process of the studies used in the current study and the studies excluded from this study in the order of their removal reasons. According to PRISMA guideline, we entered the intended data into the study and used pilot forms to collect the data required by these studies. All data related to participants, interventions performed, comparisons, outcomes, and studies design were (PICOS) gathered.

Results Systematic Reviews The Search Strategy

The following search strategy was used to search the databases:

(rs17817449 OR rs8050136 OR rs6499640 OR rs16953002 OR rs11075995 OR rs1121980 OR FTO gene polymorphism) AND (breast cancer OR Breast Tumor OR Breast Tumor, OR Tumor of Breast, Tumor of Breast OR carcinoma of Breast, OR Breast Carcinoma).

Search Result and Study selection

The search identified 534 studies that after removal of duplication, 377 studies candid for further evaluation. Abstract evaluation resulted in 168 studies for full text evaluation in which 16 studies were included in this study. Table 1 present the details of the final studies used in this analysis. Figure 5 presents the PRISMA flowchart of the studies included in this analysis.

Study Country Ethnicity Case/control OR 95%CI Result
rs9939609-rs1121980
1 Zeng (2015) China East Asia 537/537 1.9 0.90-1.57

FTO gene variants

(rs9939609rs1477196rs1121980) are

associated with the risk of breast cancer.
2 daCunha (2013) Brazil European 100/148 0.86 0.60-1.25 There was no association between rs9939609 and rs1121980 polymorphisms and the risk of breast cancer.
3 Zhao (2016) European countries European 62328/83 817 0.94 0.92-0.95 There is a significant association between rs9939609 polymorphism and the risk of breast cancer.
4 Kusinska R (2012) Poland European 134/357 1.05 0.68-1.61 Rs9939609 polymorphism is not associated with the risk of breast cancer.
5 Brooks (2012) US and Denmark European 643/1271 1.02 0.93-1.13 Rs9939609 polymorphism is not associated with the risk of breast cancer.
6 Kaklamani (2011) USA Mixed 302/349 0.506 0.30- 0.88 Rs993909 polymorphism is associated with the risk of breast cancer.
7 Mojaver (2015) Iran Middle East 99/100 1.215 0.683- 2.161

Rs9939609 polymorphism

is not associated with the risk of breast cancer.
rs1477196
1 Kaklamani (2011) [19] USA Mixed 302/349 1.447 1.13- 1.85

Rs1477196 polymorphism is strongly

associated with the risk of breast cancer.
2 Zeng (2015) [14] China East Asia 537/537 0.54 0.34- 0.86 Rs1477196 polymorphism was associated with breast cancer only in subjects with BMI less than 24
3 Akilzhanova (2012) Kazakhstan European 315/604 0.96 0.78- 1.17

Rs1477196 polymorphism is not associated

with the risk of breast cancer.
4 Mojaver (2015) Iran Middle East 99/100 0.890 0.464- 1.707

Rs1477196 polymorphism is not associated

with the risk of breast cancer.
rs11075995
1 Zeng (2015) China East Asia 537/537 0.9 0.71- 1.15

Rs1477196 polymorphism is not associated

with the risk of breast cancer.
2 Zhang (2014) China East Asia 2901/2789 1.06 0.98- 1.14 Rs11075995 polymorphism is not associated with the risk of breast cancer.
3 Garcia-Closas (2013) USA and European countries European 10706/76647 1.11 1.07- 1.15 An association was observed between rs1107599 polymorphism and the risk of breast cancer.
rs17817449
1 Long (2013) USA Africans 1113/930 1.32 1.09- 1.6

Rs1781744 polymorphism is associated with

the risk of breast cancer.
2 Zheng (2013) China, Korea, Japan and Thailand East Asia 16797/18 983 0.92 0.88- 0.97

Rs1781744 polymorphism is associated with

the risk of breast cancer.

Meta-analysis

We consider all the models of inheritance and report those that did showed association. Two polymorphisms of (rs1477196) and (rs9939609) had significant associations. No significant association was found between rs17817449 and rs11075995 polymorphisms and breast cancer.

Polymorphism rs1477196

There was an inverse association between the rs1477196 polymorphism and BC (OR 0.76 [0.64- 0.91]). There was not observable heterogeneity (I2: 0.0%, P=.867), but with a small study effect (b=1.19, P=.03) in this analysis (Figure 1 and 2).

Polymorphism rs9939609

Moreover, there was not any association between the rs9939609 polymorphism and BC (OR 0.98 [0.79- 1.2]). There was not observable heterogeneity (I2: 23.1%, P=.27) and small study effect (b=-3.817, P=.303) in this analysis (Figure 3 and 4)(Figure 5).

<fig id="figure-b5ecb639e70ea90315c6c0013590dc4c"> <label>Figure 4: Funnel Plot of the Association between rs9939609 Polymorphism and Breast Cancer</label> <caption id="caption-669d92f14da2c0b0fc5692ae0ad1df21"> <title>

<fig id="figure-2c374bcb5981f77ce6e0226fdc503e00"> <label>Figure 5: The Search Flow Chart</label> <caption id="caption-20d8a6794a7baa428b22b6c382658c4c"> <title>

Discussion

FTO gene was for the first time identified in animal models as a gene affecting programmed cell death. Mice harboring mutations in this gene have fused toes and larger thymus than most other mice [9-10]. FTO gene encodes a 2-oxoglutaratedependent oxigenase that plays a role in DNA demethylation. This gene is located on human chromosome 16q12.2. Duplication of this gene region leads to mental retardation, obesity and other abnormalities [11]. FTO gene is expressed in all body tissues; however, its highest expression has been in the brain and hypothalamus [12].

Two years after the publication of the article on the association between genetic differences of FTO gene and obesity, the researchers began their research on the association between genotype differences in this gene and the risk of cancer in obese people of different races [13]. Quantitative studies have been conducted on the association between FTO gene variants and breast cancer and various results have been obtained from these studies. The reason for part of these differences may be due to the racial differences in the study groups. For example, in a study conducted on Iranian women, Mojaver et al. concluded that there is no significant association between rs9939609 and rs1477196 polymorphisms and the risk of breast cancer [14], but in other studies, a significant association was observed between the four FTO polymorphisms (rs7206790, rs8047395, rs9939609, and rs1477196) and the risk of breast cancer [15]. In a meta-analysis conducted on the association between FTO gene rs9939609 polymorphism and breast cancer, it was found that rs9939609 polymorphism in FTO gene is associated with the risk of breast cancer in Asian race [16].

Additionally, a case-control study conducted on different races showed that the risk of breast cancer for rs1477196 polymorphism in people with homozygous dominant alleles (AA) is 2.38 times higher than individuals with genotypes GG [15]. This is while, no association was observed between this polymorphism and the risk of cancer in other studies conducted on a particular race [15-17]. The major cause of these differences may be due to racial differences in different individuals. The frequency of FTO gene polymorphisms is very different in different races. For example, the frequency of rs9930506 polymorphism in Chinese individuals was reported to be less than 0.1 [18], while the frequency of this polymorphism is approximately 0.4 in white societies.

In addition, cultural and environmental factors may also affect the role of race in the association between FTO gene and breast cancer. For example, the rate of FTO gene expression is associated with breast cancer, and recent studies have shown that dietary composition also affects the rate of FTO gene expression [3]. Differences in dietary intake in different races may justify part of difference in the results reported in previous studies on the association between FTO gene and breast cancer.

In conclusion, generally, the results of studies in this field showed that there is an association between FTO gene, obesity and breast cancer. There have been very few studies conducted in this regard. More human studies are required to assess the interface between existing mechanisms of the effects of these genes on breast cancer.

Acknowledgments

This study was funded by the National Institute of Medical Research Development (Elite Grant # 977508), Tehran, Islamic Republic of Iran.

References

07 4 03 1237-1243 33 2012 10.1007/s13277-012-0372-9 Li Guiqiong Chen Qingwei Wang Li Ke Dazhi Yuan Zhongming Tumor Biology Association between FTO gene polymorphism and cancer risk: evidence from 16,277 cases and 31,153 controls 24 17 04 1625-1638 348 2003 10.1056/nejmoa021423 Calle Eugenia E. Rodriguez Carmen Walker-Thurmond Kimberly Thun Michael J. New England Journal of Medicine Overweight, Obesity, and Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults 2 03 277-281 69 2017 10.1016/j.ihj.2017.01.014 Doaei Saeid Kalantari Naser Mohammadi Nastaran Keshavarz Tabesh Ghasem Azizi Gholamalizadeh Maryam Indian Heart Journal Macronutrients and the FTO gene expression in hypothalamus; a systematic review of experimental studies 19 1 11 51-61 10 2013 10.1038/nrendo.2013.227 Loos Ruth J. F. Yeo Giles S. H. Nature Reviews Endocrinology The bigger picture of FTO—the first GWAS-identified obesity gene 12 3 11 699-704 42 2014 10.1007/s11033-014-3817-y Hernández-Caballero Marta Elena Sierra-Ramírez José Alfredo Molecular Biology Reports Single nucleotide polymorphisms of the FTO gene and cancer risk: an overview 6 12 1163-1169 160 2010 10.1016/j.ahj.2010.08.002 Ahmad Tariq Chasman Daniel I. Mora Samia Paré Guillaume Cook Nancy R. Buring Julie E. Ridker Paul M. Lee I-Min American Heart Journal The Fat-Mass and Obesity-Associated (FTO) gene, physical activity, and risk of incident cardiovascular events in white women Cochrane Effective Practice and Organisation of Care. 2017.Suggested risk of bias criteria for EPOC reviews. http://epoc.cochrane.org/. Accessed 20 Apr 21 7 07 e1000097 6 2009 10.1371/journal.pmed.1000097 Moher David Liberati Alessandro Tetzlaff Jennifer Altman Douglas G. PLoS Medicine Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement 01 5 05 1024-1032 84 2011 10.1095/biolreprod.110.088559 Kim Bongki Kim Youngha Cooke Paul S. Rüther Ulrich Jorgensen Joan S. Biology of Reproduction The Fused Toes Locus Is Essential for Somatic-Germ Cell Interactions That Foster Germ Cell Maturation in Developing Gonads in Mice1 16 12 10 885-887 7 2011 10.1038/nchembio.687 Jia Guifang Fu Ye Zhao Xu Dai Qing Zheng Guanqun Yang Ying Yi Chengqi Lindahl Tomas Pan Tao Yang Yun-Gui He Chuan Nature Chemical Biology N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO 17 5 03 1419-1426 57 2008 10.2337/db07-1466 Freathy R. M. Timpson N. J. Lawlor D. A. Pouta A. Ben-Shlomo Y. Ruokonen A. Ebrahim S. Shields B. Zeggini E. Weedon M. N. Lindgren C. M. Lango H. Melzer D. Ferrucci L. Paolisso G. Neville M. J. Karpe F. Palmer C. N.A. Morris A. D. Elliott P. Jarvelin M.-R. Davey Smith G. McCarthy M. I. Hattersley A. T. Frayling T. M. Diabetes Common Variation in the FTO Gene Alters Diabetes-Related Metabolic Traits to the Extent Expected Given Its Effect on BMI 11 5826 05 889-894 316 2007 10.1126/science.1141634 Frayling T. M. Timpson N. J. Weedon M. N. Zeggini E. Freathy R. M. Lindgren C. M. Perry J. R. B. Elliott K. S. Lango H. Rayner N. W. Shields B. Harries L. W. Barrett J. C. Ellard S. Groves C. J. Knight B. Patch A.-M. Ness A. R. Ebrahim S. Lawlor D. A. Ring S. M. Ben-Shlomo Y. Jarvelin M.-R. Sovio U. Bennett A. J. Melzer D. Ferrucci L. Loos R. J. F. Barroso I. Wareham N. J. Karpe F. Owen K. R. Cardon L. R. Walker M. Hitman G. A. Palmer C. N. A. Doney A. S. F. Morris A. D. Smith G. D. Hattersley A. T. McCarthy M. I. Science A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity 19 4 06 971-975 38 2009 10.1093/ije/dyp162 Brennan P. McKay J. Moore L. Zaridze D. Mukeria A. Szeszenia-Dabrowska N. Lissowska J. Rudnai P. Fabianova E. Mates D. Bencko V. Foretova L. Janout V. Chow W.-H. Rothman N. Chabrier A. Gaborieau V. Timpson N. Hung R. J Smith G. D. International Journal of Epidemiology Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype 1 136 4 2015 10.4103/2277-9175.161532 Salehi Mansoor Mojaver Mahboobeh Mokarian Fariborz Kazemi Mohammad Advanced Biomedical Research Specific TaqMan allelic discrimination assay for rs1477196 and rs9939609 single nucleotide polymorphisms of FTO gene demonstrated that there is no association between these SNPs and risk of breast cancer in Iranian women 13 1 04 12 2011 10.1186/1471-2350-12-52 Kaklamani Virginia Yi Nengjun Sadim Maureen Siziopikou Kalliopi Zhang Kui Xu Yanfei Tofilon Sarah Agarwal Surbhi Pasche Boris Mantzoros Christos BMC Medical Genetics The role of the fat mass and obesity associated gene (FTO) in breast cancer risk 01 5 03 e12464 26 2016 10.1111/ecc.12464 Huang Xiaoyi Zhao Jian Yang Mingyuan Li Ming Zheng Jianming European Journal of Cancer Care Association between FTO gene polymorphism (rs9939609 T/A) and cancer risk: a meta-analysis 4049 9 4059 33 2013 Akilzhanova A Nurkina Z Momynaliev K Ramanculov E Zhumadilov Z Rakhypbekov T et al Anticancer research Genetic profile and determinants of homocysteine levels in Kazakhstan patients with breast cancer 1-6 2015 2015 10.1155/2015/101032 Zeng Xianxu Ban Zhenying Cao Jing Zhang Wei Chu Tianjiao Lei Dongmei Du Yanmin Disease Markers Association of FTO Mutations with Risk and Survival of Breast Cancer in a Chinese Population